EP3010340A2 - Zusammensetzungen und verfahren zur verstärkung einer immunantwort, zur immuntherapieverbesserung und zur erhöhung der potenz von impfstoffen - Google Patents

Zusammensetzungen und verfahren zur verstärkung einer immunantwort, zur immuntherapieverbesserung und zur erhöhung der potenz von impfstoffen

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Publication number
EP3010340A2
EP3010340A2 EP14814431.4A EP14814431A EP3010340A2 EP 3010340 A2 EP3010340 A2 EP 3010340A2 EP 14814431 A EP14814431 A EP 14814431A EP 3010340 A2 EP3010340 A2 EP 3010340A2
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EP
European Patent Office
Prior art keywords
pnp
pyrrolo
pyrimidin
inhibitor
deoxyguanosine
Prior art date
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EP14814431.4A
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English (en)
French (fr)
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EP3010340A4 (de
Inventor
Shanta Bantia
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Nitor Therapeutics
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Nitor Therapeutics
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Publication of EP3010340A2 publication Critical patent/EP3010340A2/de
Publication of EP3010340A4 publication Critical patent/EP3010340A4/de
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/08—Clostridium, e.g. Clostridium tetani
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines

Definitions

  • the technical field relates to pharmaceutical compositions comprising one or more Purine Nucleoside Phosphorylase (PNP) inhibitors and/or agents identified as endogenous adjuvants capable of providing an immune-potentiating effect in the presence of an antigen, vaccine or immunotherapy.
  • PNP Purine Nucleoside Phosphorylase
  • the field also relates to methods for preventing and treating diseases, enhancing an immune response and augmenting the potency of vaccines and immunotherapies.
  • An adjuvant is an agent administered to potentiate an immune response to an antigen and/or to modulate an immune response toward a desired immune response.
  • An endogenous adjuvant is a compound or molecule naturally occurring within a cell or tissue that likewise enhances an immune response by stimulating innate immunity, thus possessing the capacity to potentiate an effect of some triggering event or agent. Endogenous adjuvants play a central role in alerting the immune system to potential danger and in promoting response to infection, transplantation, tumor, and autoimmunity.
  • Vaccines attempt to safely elicit an immunity to pathogens that is ideally robust, protective and long-lived.
  • current formulations of many subunit vaccines provide weaker and shorter- lived immunity than natural infection.
  • adjuvants can be used to boost immunity, the adjuvants that are permitted in licensed vaccines are limited.
  • Alum a mixture of aluminum salts, was the first vaccine adjuvant that was widely utilized in vaccine preparations. It was the only vaccine adjuvant in use in the United States until 2009, when the U.S. Food and Drug Administration approved Cervarix, a human papillomavirus vaccine that contains an adjuvant designated as AS04.
  • the AS04 adjuvant is a mixture of alum and a bacterial lipid (fat) molecule that has been modified so that it does not cause disease.
  • Alum is a weak adjuvant and one thai biases responses to effector responses (Tli2) that are not protective against many pathogens.
  • Endogenous adjuvants generally have not been evaluated for their potential use in vaccines. In theory, they may allow vaccinations to safely mimic the pathway that naturally triggers immunity to many pathogens.
  • These agents also promote CD8+ T cell immune responses, which are important in immunity to many pathogens, such as viruses and tumors, but not elicited by most subunit vaccines (Rock et al. in Springer Seminars in Immunopathology (2005) 26:231-246).
  • Purine Nucleoside Phosphorylase is an enzyme involved in purine metabolism. PNP metabolizes inosine and deoxyinosine into hypoxanthine, and guanosine and deoxyguanosine into guanine; in each case creating (deoxy) ribose phosphate.
  • PNP-deficient patients exhibit significantly higher levels of plasma nucleosides including inosine, deoxyinosine, guanosine and deoxyguanosine when compared to PNP-normal subjects (Markert in Immunodeficiency Review (1991) 3:45-81), and further exhibit elevated levels of erythrocyte deoxyguanosine triphosphate (dGTP) and nicotinamide adenine dinucleotide (NAD).
  • dGTP erythrocyte deoxyguanosine triphosphate
  • NAD nicotinamide adenine dinucleotide
  • Plasma deoxyguanosine (the only clinically measurable nucleoside) and intracellular dGTP are elevated in patients treated with PNP inhibitors (Bantia and Kilpatrick in Current Opinions in Drug Discovery & Development (2004) 7: 243-247).
  • Deoxyguanosine was also elevated in mouse plasma after treatment with PNP inhibitor (Bantia et al. in International Immuno- pharmacology (2001) 1: 1199-1210 and (2010) 10:784-790).
  • nucleoside pools A major source of nucleoside pools comes from the breakdown of RNA and DNA during normal cell turnover, cellular injury or cell death due to infection. Normally the nucleosides deoxyguanosine, inosine, deoxyinosine, and guanosine are present at very low to undetectable levels in the plasma because PNP is an extremely efficient catalyst and rapidly breaks down inosine and deoxyinosine to hypoxanthine, and guanosine and deoxyguanosine to guanine and sugar 1- phosphate. In the presence of a PNP inhibitor or due to a PNP deficiency, however, these nucleosides become elevated.
  • ANA773 an oral pro-drug of isatoribine, has been demonstrated to induce endogenous interferon-a (IFN-a) of multiple subtypes in healthy volunteers.
  • IFN-a interferon-a
  • ANA773 demonstrated a dose-dependent reduction in HCV RNA (Bergmann et al. in Aliment Pharmacol Ther (2011) 34:443-453; International patent number WO2005025583A2).
  • TLR7 Toll-Like Receptor 7
  • PRR pathogen recognition receptors
  • PRR's for example retinoic acid inducible gene I (RIGI) like receptors (RLR), nucleotide binding oligomerization domain (NOD)-like receptors (NLR) and c- type lectin receptors (CLR).
  • RIGI retinoic acid inducible gene I
  • RLR retinoic acid inducible gene I
  • NOD nucleotide binding oligomerization domain
  • NLR nucleotide binding oligomerization domain
  • CLR c- type lectin receptors
  • TLRs and other PRRs Direct or indirect stimulation of TLRs and other PRRs causes the release of multiple cytokines including type 1 and type 2 interferons, the induction of pathways and enzymes that destroy intracellular pathogens, the activation of a variety of cellular responses, and the priming of the adaptive response by activation of immature dendritic cells, inducing their differentiation into professional antigen- presenting cells.
  • cytokines including type 1 and type 2 interferons
  • the induction of pathways and enzymes that destroy intracellular pathogens the activation of a variety of cellular responses
  • the priming of the adaptive response by activation of immature dendritic cells inducing their differentiation into professional antigen- presenting cells.
  • At least eleven different TLR genes have been identified in humans. It appears that through stimulation of innate immunity by activating TL , it is possible to prevent or reverse otherwise lethal viral infections in various acute infection models in mice,
  • Methyl inosine monophosphate a particular inosine analog, has also shown immune enhancing effects and demonstrated antiviral and antibacterial effects (Mishin et al. in Antiviral Research (2006) 71:64-68).
  • compositions and methods which exploit the endogenous adjuvant response to enhance the immunogenicity of an antigen and to augment the potency of vaccines and cancer immunotherapies.
  • present disclosure provides articles of manufacture, methods and compositions effective for increasing levels of the nucleosides inosine, deoxyinosine, guanosine and deoxyguanosine, and for increasing levels of the nucleotides dGTP and NAD in a subject.
  • compositions and methods for inhibiting PNP to effectuate an increase in inosine, deoxyinosine, guanosine, deoxyguanosine NAD and dGTP pools in a subject are described and detailed.
  • These endogenous substances behave as endogenous adjuvants and can act as immune-enhancers in the presence of an antigen or vaccine and therefore act to enhance the potency of vaccine and immunotherapies, including specifically cancer immunotherapy.
  • Such compositions and methods were not previously appreciated in the art.
  • compositions, kits and methods useful for inhibiting PNP in combination with one or more exogenously administered agents that have been identified as endogenous adjuvants are also described.
  • the agents include, for example, inosine, deoxyinosine, guanosine, deoxyguanosine, NAD and dGTP, individually or in any combination.
  • the compositions act as immune-enhancers in the presence of an antigen or vaccine and act to enhance the potency of the vaccine and/or immunotherapy. Such compositions and methods were not previously appreciated in the art.
  • One embodiment provides methods of enhancing the potency of vaccine or cancer immunotherapies or the immunogenicity of an antigen by increasing an amount of at least one endogenous adjuvant, the method comprising administering a pharmaceutically effective amount of a purine nucleoside phosphorylase (PNP) inhibitor to a subject requiring treatment.
  • PNP purine nucleoside phosphorylase
  • the methods may further comprise administering an agent identified as an endogenous adjuvant in conjunction with administration of the PNP inhibition.
  • Administration "in conjunction with” may be at the same time, in the same treatment cycle or subsequent to administration of the PNP inhibitor.
  • PNP purine nucleoside phosphorylase
  • compositions effective for enhancing the potency of vaccines and cancer immunotherapies in a subject comprise at least one PNP inhibitor and at least one agent identified as an endogenous adjuvant.
  • compositions may be formulated as oral dosage forms, parenteral dosage forms or topical dosage forms, and in specific embodiments the oral dosage form is formulated to provide delayed release of the PNP inhibitor relative to the agent identified as an endogenous adjuvant.
  • Kit embodiments are also disclosed.
  • the kits comprise a first dosage form and a second dosage form, the first dosage form comprising a PNP inhibitor and the second dosage form comprising at least one agent identified as an endogenous adjuvant.
  • Fig. 1 Depicts a schematic illustration of the relationship between PNP inhibition and levels of inosine, deoxyinosine, guanosine, deoxyguanosine, and nucleotide dGTP levels.
  • Fig. 2. Sets forth data demonstrating activity of the NTROOl, inosine and guanosine as single agents and in combinations on seven different human TLRs (TLR2, 3, 4, 5, 7, 8 and 9) as potential agonists.
  • Fig. 3. Shows serum tetanus toxoid antibody titers on day 38 in control, NTROOl- and NTR002-treated mice groups in the tetanus toxoid mouse model.
  • Fig. 4. Shows serum interferon-g levels on day 30 in control and NTROOl - and NTR002- treated mice groups in the tetanus toxoid mouse model.
  • Fig. 5 Illustrates effect of PNP inhibitor NTROOl and chemotherapeutic
  • Fig. 6 Illustrates effect of PNP inhibitor NTROOl and chemotherapeutic
  • Fig. 7 Illustrates effect of PNP inhibitor NTROOl on weight loss in the mouse model of L. Monocytogenes infection.
  • Fig. 8 Illustrates effect of PNP inhibitor NTROOl on survival in the mouse model of L. Monocytogenes infection.
  • Fig. 9 Illustrates effect of PNP inhibitor NTR002 on weight loss in the mouse model of L. Monocytogenes infection.
  • Fig. 10 Illustrates effect of PNP inhibitor NTR002 on survival in the mouse model of L. Monocytogenes infection.
  • New generation vaccines will increasingly comprise highly purified recombinant proteins. Unfortunately, these antigens are often poorly immunogenic. Therefore, adjuvants will be required to enable these proteins to become effective vaccines. Stimulation of the innate immune response is now known to have an important role in the evolution of the adaptive immune response. Hence, identification and inclusion of immune potentiators (also termed adjuvants), which trigger an early innate immune response to aid in the generation of robust and long lasting adaptive immune responses is crucial to vaccine effectiveness.
  • immune potentiators also termed adjuvants
  • compositions and methods effective for enhancing the potency of a vaccine or an immunotherapy administered to a subject as part of a prevention or treatment regimen A broad embodiment is directed to a method comprising: administering a composition comprising a pharmaceutically effective amount of a purine nucleoside phosphorylase (PNP) inhibitor to a subject in conjunction with the vaccine or immunotherapy.
  • PNP purine nucleoside phosphorylase
  • the vaccine or immunotherapy may be for treatment or prevention of infectious disease or treatment or prevention of cancer.
  • the immunotherapy comprises administration of at least one indoleamine-pyrrole 2,3- dioxygenase (IDOl) inhibitor and/or one checkpoint modulator selected from the group consisting of CTLA-4 antagonists, GITR agonists, OX40 agonists, LAG-3 antagonists, TIM- 3 antagonists and PD-1 antagonists, PDL-1 antagonists and CD- 27 agonists.
  • IDOl indoleamine-pyrrole 2,3- dioxygenase
  • checkpoint modulators selected from the group consisting of CTLA-4 antagonists, GITR agonists, OX40 agonists, LAG-3 antagonists, TIM- 3 antagonists and PD-1 antagonists, PDL-1 antagonists and CD- 27 agonists.
  • Very specific known drugs which act as checkpoint modulators include ipilimumab,lambrolizumab (anti-PDl), anti-programmed death ligand-1 (antiPDl-1), and CDX-1127.
  • Immunotherapy by administration of one or more Toll-like Receptor agonists may also be potentiated by administration of a PNP- inhibitor.
  • TLR agonists include TLR 2, TLR3, TLR4, TLR5, TLR7, TLR8, and TLR9 agonists.
  • TLRs play a critical role in the eariy innate immune response to invading pathogens by sensing microorganisms, and are also involved in sensing endogenous danger signals.
  • TLRs recognize highly conserved structural motifs known as pathogen-associated microbial patterns (PAMPs), which are exclusively expressed by microbial pathogens, and/or danger- associated molecular patterns (DAMPs) that are endogenous molecules released from necrotic or dying cells. Stimulation of TLRs by the corresponding PAMPs or DAMPs initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-KB and interferon regulatory factors (IRFs). Signaling by TLRs results in a variety of cellular responses including the production of interferons (IFNs), release of proinflammatory cytokines and release of effector cytokines that direct the adaptive immune response.
  • IFNs interferons
  • PNP (sometimes referred to as PNPase) deficiency is known to result in an increase in levels of the substrates of the enzyme.
  • PNP substrates include inosine, deoxyguanosine, deoxyinosine and guanosine.
  • PNP inhibition also leads to accumulation of intracellular dGTP and NAD (Markert in Immunodeficiency Review (1991) 3:45-81).
  • nucleosides as well as nucleotides dGTP and NAD can act as endogenous adjuvants similar to other purines known as putative endogenous adjuvants, such as uric acid, ATP and adenosine. These endogenous adjuvants can then activate the immune system through TLRs and/or other PRRs in the presence of an appropriate antigen/vaccine or cancer immunotherapy.
  • Fig. 1 is a schematic presentation of the role of PNP in purine metabolism which illustrates the relationship between PNP inhibition and observed increases in inosine, deoxyinosine, guanosine, deoxyguanosine, and dGTP levels.
  • PNP-deficiency is an extremely rare autosomal recessive metabolic disorder which results in severe combined immunodeficiency and a profile of symptoms associated with immunodeficiency, such as depletion of T-cells, decline of lymphocyte activity, and an abrupt proliferation of both benign and opportunistic infections. Due to the rarity of the condition, investigators have developed a knock-out mouse model. PNP-deficient patients and PNP-deficient mice exhibit high levels of the PNP-substrate nucleosides as well as nucleotides NAD and dGTP. Patients treated with PNP inhibitor or animals treated with PNP inhibitor also show increases in plasma levels of deoxyguanosine.
  • nucleoside pools A major source of nucleoside pools comes from the breakdown of RNA and DNA during cellular injury or cell death. Normally, the nucleosides deoxyguanosine, inosine, deoxyinosine, and guanosine are present at very low or undetectable levels in the plasma because PNP rapidly breaks down inosine and deoxyinosine to hypoxanthine, and breaks down guanosine and deoxyguanosine to guanine and sugar 1 -phosphate. In the presence of PNP inhibitor or PNP deficiency these nucleosides are elevated.
  • the inventive compositions may further comprise at least one agent identified as an endogenous adjuvant.
  • Guanosine analogs such as isatoribine (7-thia, 8-oxoguanosine) and loxorabine (7-allyl, 8-oxo guanosine) have demonstrated immune -potentiating effects.
  • In- vitro studies with some guanosine analogs have shown activation of immune cells, for example dendritic cells and natural killer cells to produce ifn-gamma which is mediated through Toll-Like Receptor 7 (TLR7).
  • TLR7 Toll-Like Receptor 7
  • Embodiments of the present invention therefore provide methods for preventing and treating diseases which recognize and exploit the natural endogenous adjuvant response. Controlling/modulating the levels of endogenous adjuvants provides a novel means to enhance immunogenicity of an antigen and augment potency of vaccines and cancer immunotherapies. Further, identification of endogenous adjuvants triggered in response to certain pathogens could provide novel exogenous adjuvants which may be administered in conjunction with vaccine and immunotherapy to enhance an immune response and augment potency.
  • NRR002 also known as Ulodesine l,5-dihydro-7-[[(3R,4R)-3-hydroxy-4-(hydroxymethyl)pyrrolidin-l- yl]methyl]-4H-pyrrolo[3,2-d]pyrimidin-4-one
  • Formula II also known as Forodesine 7-[(2S,3 l S , ,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2- pyrrolidinyl]-l,5-dihydro-4H-pyrrolo[3,2-d]pyrimidin-4-one
  • Formula III have been shown to inhibit PNP.
  • transition state analogs have been studied as PNP inhibitors (Evans et al. in Organic Letters (2003) 5:3639; Taylor et al. in Journal of American Chemical Society (2007) 129:6984; Evans et al. in Journal of Medicinal Chemistry (2003) 46:5271; Castilho et al. in Bioorganic & Medicinal Chemistry (2006) 14:516; Schramm et al. in Journal of Biological Chemistry (2007) 282:28297; and Bantia et al. in International Immunopharmacology (2010) 784 and (2001) 1: 1199-1210; Kicska et al. in Proceedings of National Academy of Sciences (2001) 98:4593- 4598).
  • Non-limiting examples of PNP inhibitors include those disclosed in U.S. Patent Numbers. 4,985,433; 4,985,434, 5,008,265; 5,008,270; 5,565,463 7,427,624, 5,721,240, 5,985,848, 7,390,890 and the continuation patents that are referenced therein, 7,109,331 , 8,283,345, 8,173,662 and 7,553,839, and International Patent Number WO2008/030119 and EP2395005, the disclosures of which are also incorporated herein in the entirety by this reference.
  • PNP inhibitor includes compounds/molecules that inhibit PNP by any direct or indirect mechanism. It is entirely predictable that any agent shown to be a PNP inhibitor will be effective in the present methods; however in specific embodiment an effective PNP inhibitor comprises a transition state analog of PNP having an in-vitro inhibitory constant Ki value of less than about 5 x 10 " ° M. Compositions having in-vitro inhibitory constant (Ki) values of less than about 5 x 10 "6 M, typically less than about 1 X 10 "7 M, and preferably less than 5 X 10 "8 M are preferred for in vivo use. One embodiment relates to the use of PNP inhibitors as immune-potentiators in the presence of an antigen.
  • kits and compositions for inhibition of PNP to effectuate increases in the level of one or more of inosine, deoxyinosine, guanosine, deoxyguanosine, NAD and dGTP are provided.
  • Yet another embodiment is directed to enhancing the potency of vaccines and immunotherapies.
  • the potency of vaccines and immunotherapies for the prevention and treatment of infectious diseases and cancer may be enhanced by effectuating an elevation in inosine, deoxyinosine, guanosine, deoxyguanosine, NAD and/or dGTP levels, each of which individually or in combination can act as an endogenous adjuvant effective for stimulating the immune system.
  • compositions comprising at least one agent identified as an endogenous adjuvant.
  • an agent may be identified as an endogenous adjuvant if endogenous levels of the agent in a subject increase in response to administration of a PNP inhibitor to the subject. In some aspects the increase is associated with an immune-response stimulating effect.
  • the compositions may additionally comprise one or more PNP inhibitors.
  • the agent is selected from inosine, deoxyinosine, guanosine, deoxyguanosine, NAD, dGTP and combinations thereof.
  • the present disclosure also provides articles of manufacture for increasing nucleoside levels in a subject.
  • the nucleosides are selected from the group consisting of inosine, deoxyinosine, guanosine, deoxyguanosine, and combinations thereof.
  • Articles of manufacture for increasing nucleotides NAD and/or dGTP levels in a subject are also provided.
  • aarticles of manufacture enhance the potency of vaccines and cancer immunotherapies related to increases in nucleosides, inosine, deoxyinosine, guanosine, and deoxyguanosine, and nucleotides NAD and dGTP levels.
  • the article of manufacture comprises at least one reservoir containing a composition comprising one or more of compounds structurally depicted by formula I, II, and III, trivial variants thereof, PNP inhibitors listed in U.S. Patent Numbers 5,985,848, 6,066,722 and 7,553,839, and International Patent Number WO2008/0301 19, and agents identified as an endogenous adjuvant including but not limited to inosine, deoxyinosine, guanosine, deoxyguanosine, NAD and dGTP.
  • the articles of manufacture may be packaged with indications for various disorders that the compositions are contemplated to treat.
  • the articles of manufacture may comprise a unit dose of a composition according to the invention, and an indication that the unit dose is capable of treating a certain disorder.
  • Compounds of formula I, II and III are 9-deazahypoxanthine derivatives.
  • the compound of formula I is known in the art as Ulodesine and may be referred to herein as NTR002.
  • the compound of formula II is known in the art as Forodesine and may be referred to herein as NTR001.
  • Compounds of formula I, II, III and related compounds are described in U.S. Patent Numbers 5,985,848, 6,066,722, and 7,553,839 and International Patent Number WO2008/030119.
  • these compounds can exist as a pharmaceutically acceptable salt.
  • these compounds can exist as a tautomer.
  • these compounds can exist as a solvate
  • these compounds can exist as a hydrate.
  • these compounds can exist as a prodrug.
  • the agent identified as an endogenous adjuvant is selected from the group consisting of guanosine, inosine, deoxyinosine, deoxyguanosine, nicotinamide adenine dinucleotide, deoxyguanosine triphosphate, pro-drugs thereof, and combinations thereof.
  • the agent is guanosine or a pro-drug thereof. Analogs of guanosine with retention of efficacy are also contemplated as within the scope of the invention.
  • Administration may be via an enteral or parenteral or topical route or any other known method of administration in the literatures.
  • administration may be oral.
  • Administration "in conjunction with” according to the present invention may mean simultaneous as part of the same composition, or it may mean simultaneous in two distinct dosage forms, or in some embodiments it may mean in tandem separated by seconds, minutes, hours or days.
  • the agent identified as an endogenous adjuvant will be administered after the PNP inhibitor.
  • PNP inhibitor will be administered one hour or more after the agent identified as an endogenous adjuvant. All these exemplary embodiments fall within the scope of "in conjunction with.”
  • an oral, parenteral or topical dosage form of the compositions of PNP-inhibitor and endogenous adjuvant are formulated to provide delayed release of the PNP inhibitor relative to release of the endogenous adjuvant.
  • the PNP-inhibitor may be integrated into a delayed release matrix while the endogenous adjuvant may be layered over the delayed release matrix.
  • Such delayed release forms are well known in the art (see Allen and Ansel, "Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems" 10 th Edition, 2014 Lippincott, Williams and Wiklins, the entire contents of which is incorporated herein by this reference).
  • kits may be provided comprising a first dosage form and a second dosage form, the first dosage form comprising a PNP inhibitor and the second dosage form comprising at least one agent identified as an endogenous adjuvant.
  • the article of manufacture may contain a therapeutically effective amount of one or more of compounds of formula I, II, III and related compounds described in U.S. Patent Numbers 5,985,848, 6,066,722 and 7,553,839 and International Patent Number WO2008/030119, and one or a combination of inosine, deoxyinosine, guanosine, deoxyguanosine, and dGTP.
  • the article of manufacture may further comprise, consist essentially of or consist of one or more additional active agents in combination with compounds of formula I, II, III and related compounds described in U.S. Patent Numbers 5,985,848, 6,066,722 and 7,553,839, and International Patent Number WO2008/030119, and optionally one or a combination of inosine, deoxyinosine, guanosine, deoxyguanosine, NAD and dGTP.
  • the article of manufacture may further comprise, consist essentially of or consist of one or more additional active agents in combination with compounds of formula I, II, III and related compounds described in U.S. Patent Numbers 5,985,848, 6,066,722 and 7,553,839, and International Patent Number WO2008/030119,
  • additional active agents include, but are not limited to, analgesic agents, anti-inflammatory agents, anti- infective agents, chemo therapeutic agents, other immune enhancers or immunotherapies and agents that inhibit purine metabolism or other active agents know in the art.
  • the present disclosure provides methods for increasing inosine, deoxyinosine, guanosine deoxyguanosine, NAD and dGTP levels in a subject receiving a vaccine or cancer immunotherapy.
  • a "significant impact" occurs when the patient exhibits symptoms associated with a reduction in lymphocytes not due to any underlying disease condition.
  • the patient is contemplated for immunotherapy for the treatment of cancer, and in very specific embodiments the cancer is a non hematologic cancer.
  • the present disclosure further provides methods for increasing inosine, deoxyinosine, guanosine deoxyguanosine, NAD and dGTP levels in a subject receiving vaccine or cancer immunotherapy, the method comprising administering to the subject a therapeutically effective amount of one or more compounds of the formula I, II and III, a trivial variant thereof, or a pharmaceutically acceptable salt, tautomer, isomer, prodrug, solvate or hydrate thereof and an optional pharmaceutically acceptable carrier.
  • the present disclosure provides for methods for enhancing the immune response in a subject receiving vaccine or cancer immunotherapy, the method comprising administering to the subject a therapeutically effective amount of compound of the formula I, II and III or a pharmaceutically acceptable salt, tautomer, isomer, prodrug, solvate or a hydrate thereof, one or combination of the four nucleosides inosine, deoxyinosine, guanosine and deoxyguanosine, and nucleotides NAD and dGTP and an optional pharmaceutically acceptable carrier.
  • effective dosages of the compounds of the invention can be determined by comparing their in vitro activity to their respective in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art; for example, as described in U.S. Patent Number 4,938,949, the entire disclosure of which is incorporated herein by reference.
  • Example 1 demonstrate that guanosine, which is one of the nucleoside that is elevated when PNP is inhibited, activate TLR2 and TLR4. Activation of TLR2 and TLR4 results in immune potentiating effects as it leads to expression of transcription factors (like NF-kB ans IRF-3) resulting in expression of inflammatory cytokines and other cellular activation events.
  • Examples 2, 3 and 4 demonstrate the immune potentiating activity of PNP inhibitor in various in- vivo mouse models.
  • Formulas I, II and III include trivial variants thereof, the term "trivial" being with respect to pharmaceutical efficacy.
  • NTR001 is depicted structurally as Formula II
  • NTR002 is depicted structurally as Formula I.
  • TLR Toll-Like Receptor
  • TLRs play a critical role in the early innate immune response to invading pathogens by sensing microorganism and are involved in sensing endogenous danger signals.
  • TLRs recognize highly conserved structural motifs known as pathogen-associated microbial patterns (PAMPs), which are exclusively expressed by microbial pathogens, or danger-associated molecular patterns (DAMPs) that are endogenous molecules released from necrotic or dying cells. Stimulation of TLRs by the corresponding PAMPs or DAMPs initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-KB and interferon regulatory factors (IRFs).
  • PAMPs pathogen-associated microbial patterns
  • DAMPs danger-associated molecular patterns
  • Stimulation of TLRs by the corresponding PAMPs or DAMPs initiates signaling cascades leading to the activation of transcription factors, such as AP-1, NF-KB and interferon regulatory factors (IRFs).
  • IRFs interferon
  • TLRs Signaling by TLRs result in a variety of cellular responses including the production of interferons (IFNs), proinflammatory cytokines and effector cytokines that direct the adaptive immune response.
  • IFNs interferons
  • proinflammatory cytokines proinflammatory cytokines
  • effector cytokines that direct the adaptive immune response.
  • TLR2 seven different human TLRs
  • TLR stimulation is tested by assessing NF- ⁇ activation in HEK293 cells expressing a given TLR.
  • the Secreted Embryonic Alkaline Phosphatase (SEAP) reporter is under the control of a promoter inducible by the transcription factor NF-KB. This reporter gene allows the monitoring of signaling through the TLR, based on the activation of NF- ⁇ .
  • the compounds are evaluated at one concentration and compared to control ligands. This step is performed in triplicate.
  • Guanosine is an agonist of TLR2 and TLR4 receptors.
  • TLR2 and TLR4 results in immune activation and hence guanosine in the presence of PNPi (to prevent breakdown of guanosine) or PNPi alone (elevates guanosine in vivo) would be beneficial as vaccine adjuvants or to enhance potency of immunotherapies for the prevention and the treatment of cancer and infections.
  • Alum Aluminium based mineral salts
  • PNP inhibitors are novel small molecule that can potentially act as an adjuvant.
  • Tetanus toxoid was used to vaccinate mice thrice, two weeks apart. Mice were treated by oral administration of compounds NTROOl and NTR002 and serum was collected at various time points for antibody titer and interferon-g analysis. Mice in Groups 2-6 (Table 2) are vaccinated subcutaneously with 0.1 ml tetanus toxoid vaccine on DAYS 0, 14 and 28. Mice in Group 1 (Table 1) received no vaccine. Treatments are done as shown in Table 1. Antibody titers for DAYS 38 are determined by ELISA using tetanus toxoid coated microtiter plates and anti-mouse conjugate. Sera from DAY 30 are assayed by ELISA for interferon-g.
  • PNP inhibitors NTROOl and NTR002 enhanced the potency of the tetanus toxoid vaccine by increasing the antibody titers and importantly, the PNP inhibitors induced Thl responses associated with the induction of interferon- g.
  • the PNP inhibitors represent a novel approach to enhancing both cellular and humoral immunity and may be useful as a vaccine adjuvant.
  • NTR001 demonstrated significant efficacy in the syngeneic mouse melanoma model. Combinations of NTR001 with other anticancer and cancer immunotherapies such as checkpoint agonist, Yervoy, anti- PD1, etc. should be pursued. Treatment with alternate doses and dose schedule is also warranted.
  • mice are infected with lxlO 6 CFU of L. monocytogenes (ATCC Strain35152, hemolytic substrain) by intravenous route.
  • the treatment of various groups is initiated -4 hr prior to infection except for Groups 3 and 7 for which treatment was initiated 2 days prior to infection and group 6 and 10 for which treatment was initiated 5 days prior to infection. Weight and survival are the end points of the study.
  • Treatment arms were as follows:
  • PO oral gavage
  • IP intraperitoneal injection
  • DW drinking water
  • NTR001 and NTR002 demonstrated significant benefit in mouse model of L. monocytogenes infection. Combinations of NTR001 and NTR002 with other antibacterial agents should be pursued. Treatment with alternate doses and dose schedule is also warranted.
  • Claims or descriptions that include "or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the invention also includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims or from the description above is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more elements, limitations, clauses, or descriptive terms, found in any other claim that is dependent on the same base claim.
  • claims recite a composition it is to be understood that methods of using the composition for any of the purposes disclosed herein are included within the scope of the invention, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.
  • Methods can include a step of providing a subject suffering from a targeted disease or condition, or being at risk of developing a disease or condition, a step of diagnosing a subject as having a targeted disease or condition or as being at risk of a disease or condition, and/or a step of selecting a subject for which an inventive composition or method would be suitable.
  • a step of providing a subject suffering from a targeted disease or condition, or being at risk of developing a disease or condition a step of diagnosing a subject as having a targeted disease or condition or as being at risk of a disease or condition, and/or a step of selecting a subject for which an inventive composition or method would be suitable.

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